The two objectives of this proposal are to elucidate the regulatory mechanisms controlling fetal and neonatal erythropoiesis, and to apply that knowledge to investigations of the pathogenesis and treatment of fetal and neonatal erythropoietic failure. Four varieties of erythropoietic failure will be investigated: 1) the hyporegenerative "anemia of prematurity"; 2) a hyporegenerative anemia seen in some patients with bronchopulmonary dysplasia (BPD); 3) the "late" anemia of Rh hemolytic disease; and 4) the Diamond Blackfan Syndrome. The studies are divided into five specific aims: 1) to improve understanding of the unique aspects of fetal erythropoietic regulation, using progenitor cell cultures to quantify mRNA and protein production of erythropoietic factors; 2) to determine the pathogenesis and evaluate treatment of the "anemia of prematurity" by determining the kinetics of hypoxemia-stimulated production of erythropoietin mRNA and protein by macrophages from preterm and term fetuses; determining the mechanisms responsible for the neutropenia in preterm infants treated with recombinant erythropoietin, using clonogenic assays and DNA amplification; and evaluating the effect of administering recombinant erythropoietin plus a recombinant erythroid burst-promoter as treatment for the "anemia of prematurity"; 3) to determine if the mechanism responsible for anemia in a sub-set of patients with BPD involves abnormal production of erythroid growth factors or growth factor inhibitors, and to evaluate the effect of administering recombinant erythropoietin as treatment; 4) to determine if the mechanism responsible for the "late" anemia of Rh hemolytic disease involves inappropriately low production of erythropoietin, and to evaluate the effect of administering recombinant erythropoietin as treatment; and 5) to assess two candidate genes potentially responsible for the Diamond Blackfan Syndrome in a unique Utah kindred.